This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Human epidermal growth factor receptor 2 (HER2) is a member of the human epidermal growth factor receptor kinases (other members include EGFR or HER1, HER3, and HER4) that is involved in signaling cascades for cell growth and differentiation. It is well established that HER2-mediated heterodimerization has important implications in cancer. Deregulation of signaling pathways and overexpression of HER2 is known to occur in cancer cells. We have designed peptidomimetics that inhibit signaling for cell growth. The central hypothesis is that peptidomimetics designed based on the structure of the HER2-herceptin complex will inhibit the HER2-mediated signal for cell growth. To understand the molecular mechanism of signaling mediated by HER2 protein, a peptidomimetic HERP5 was used. Thea objectives of this study are (a) to evaluate the binding properties of HERP5 to HER2 on the cell surface;(b) to evaluate the binding of fluorescently labeled HERP5 to domain IV of HER2 protein;c) to evaluate the binding of HERP5 and its analogs with HER2 extracellular domain using structural biology techniques;and d) to model the dimerization of HER2 with other receptors using computational methods. Binding of fluorescently labeled HERP5 to HER2 protein was evaluated by fluorescence assay, microscopy, and circular dichroism spectroscopy. Results indicated that HERP5 binds to the extracellular region of the HER2 protein. A model was proposed for HER2-EGFR dimerization and possible blocking by HERP5 peptidomimetic using a protein-protein docking method. Future studies will be focused on HER2 protein expression, purification, and blocking of HER2-EGFR interactions using surface plasmon resonance technique and structural biology methods.